Arthritis and other related inflammatory conditions are generally debilitating, painful diseases that affect the joints of a significant portion of the human and other animal populations. As a result of the wide spread occurrence of such diseases, considerable medical effort has been directed towards producing and identifying therapies that are able to at least relieve some of attendant pain, and produce regression of the malady.
As a result of this work, many compounds have been found to be useful in the treatment of such inflammatory diseases with varying degrees of success being achieved in relieving the pain of the disease and the restoration of the affected joints to normal function.
One of the earliest compounds to be used to treat inflammatory disease, which was found to have some effect in relieving pain, was salicylic acid. Unfortunately, this compound was found to be excessively irritating to the gastrointestinal tract. Accordingly, many derivatives of salicylic acid were evaluated for anti-inflammatory activity which resulted in the identification of aspirin as an effective and relatively safe anti-inflammatory compound.
Since the discovery of aspirin, many other compounds have been produced which are claimed to be more effective than aspirin. These include such compounds as the phenylacetic acids exemplified by ibuprofen and more recently identified compounds such as naproxen and sulindac. Strong anti-inflammatory potency has been achieved with the corticosteroids (e.g. hydrocortisone, dexamethasone, prednisolone, methyl prednisolone, betamethasone, paramethasone, and triamcinolone) as their water soluble and insoluble derivatives and these are also widely prescribed.
However, all of these prior art compounds and compositions whilst displaying satisfactory analgesic anti-inflammatory properties, in that they relieve joint pain to a certain extent in most cases, any beneficial effect that they have in restoring joint function is usually only transitory.
Furthermore, prolonged therapy with these prior art compounds and compositions while providing continuing pain relief for many sufferers can lead to breakdown and failure of connective tissues, particularly articular cartilage which in fact may exacerbate the problem. Examples of this phenomenon are described by: Newman and Ling, Lancet Jul. 6, 11-14, 1985; Watson, Rheum. Rehab., 15, 26-30, 1976; McKenzie, Horsburgh, Ghosh and Taylor Ann. Rheum. Dis. 35, 487-417, 1976; Burkhardt and Ghosh, Seminars in Arthritis and Rheumatism, Suppl. 1, 17, 1-34, 1987. Corticosteroids, while still extensively used as anti-inflammatory agents for intra-articular treatment of severe arthropathies, are amongst the most potent inhibitors of connective tissue growth, repair and biosynthesis of matrix components (see Silbermann et al., Bone and Mineral 2, 87-106, 1987; Rimza, AM. J. Dis. Child. 132, 806-810, 1978; Canalis, Endocrinology, 112, 931-939, 1983; Reynolds, Exp. Cell. Res. 41, 174-189, 1966; Oikarinen, Biochem. Pharmacol, 26, 875-879, 1977, Silbermann et al., Growth, 47, 77-96, 1983, Saarni, Biochem. Pharmacol, 26, 1961-1966, 1977 Olah, and Kostenszky, Acta. Biol. Acad. Sci, Hung. 27, 129-134, 1976). Many clinical reports have appeared condemning the long term uses of these agents, reviewed by Neustadt, in "Osteoarthritix, Diagnosis and Management, Chapter 19, Eds. Moskowitz, Howell, Goldberg, Mankin, W. B. Saunders and Co. 1984).
In more recent times, considerable research has been conducted to elucidate the causative mechanism of arthritis and other inflammatory diseases. Included in this work has been investigations of the normal joint function and the recognition of pathological signs associated with the disease.
As a result of the aforementioned work, hyaluronate has been identified as one of the major non-protein components present in the synovial fluid of animal joints and it has been found to be largely responsible for the rheological properties of synovial fluid, these properties being dependent on the concentration and molecular size of the hyaluronate. It should be noted that hyaluronate is a naturally occurring glycosaminoglycan present in many tissues, in addition to the synovial fluid, of the bodies of animals.
As a consequence of this latter finding, work has been directed towards determining the role of hyaluronate in normal joint function and the changes, if any, that occur in diseased joints. The findings of this latter work has led to the suggestion that application of hyaluronate, obtained from disease free tissues, to diseased joints may assist in restoring normal joint function and the relief of pain associated with the diseased joints.
However, it would appear that the results of such treatments in the past have been disappointing since the newly introduced hyaluronate is itself rapidly broken down by the inflammatory cells free radicals and their enzymes within the joint thereby losing its beneficial properties.
This finding also suggests that even if hyaluronate of the correct molecular size range was applied to diseased joints, it is likely that only temporary relief would result unless the hyaluronate was provided to the joint on a continuous basis.
Moreover, it has been found in vitro by the present inventors that hyaluronate synthesized by cells derived from arthritic synovial joints is of a smaller molecular size than that normally secreted. This finding suggests that to further restore normality of function the production of hyaluronate within the joints should be controlled to ensure that the hyaluronate produced is of the correct molecular size range.
In accordance with the finding of molecular size reduction of hyaluronate in diseased joints, as well as the rapid breakdown and loss of normal size by hyaluronate when introduced into the pathological joint, and the benefit to be gained by controlling the synthesis of hyaluronate of the correct molecular size range, the present inventors have surprisingly found that by combining hyaluronate with compounds which suppress the migration into the joint of inflammatory cells, the release by these cells of inflammatory mediators, free radicals and proteolytic enzymes, then the integrity and biosynthesis of the hyaluronate may be preserved.